Identification of the components, targets, and magnitude of an effective immune response to HIV are important steps toward the development of an effective vaccine. Although patients with normal CD4+ T cell counts and low levels of plasma virus are a heterogeneous group, a small subgroup of patients with truly non-progressive HIV infection and restriction of virus replication likely hold important clues to the basis of an effective immune response to HIV. For this reason we have focused considerable attention on groups of such patients who are felt to have immune system mediated restriction of virus replication. It now appears clear that a large fraction of patients previously considered long term non-progressors (LTNPs) ultimately show a decline of CD4+ T cell numbers. A small subpopulation (fewer than 0.8% of HIV infected individuals) shows no signs of progression over a 10 year period. We have assembled a unique cohort of such patients with non-progressive disease. Many of these patients have been infected for 15 years with no CD4+ T cell decline, plasma virus below the levels of detection, and no virus cultured in routine CD8+ T cell depleted cultures. We have previously shown that these patients are unique in the ability of their CD8+ T cells to restrict HIV replication when engrafted into experimental animals. Cells from these patients, all of whom are untreated, are being used to systematically dissect the mechanisms of immune mediated restriction of virus replication.HIV specific CD8+ T cell responses of these patients were studied by a combination of standard cytotoxic T cell (CTL) assays, flow cytometric assays, and T cell receptor (TCR) repertoire analysis in comparison with patients with progressive disease. Very high frequencies (0.8-18.0%) of circulating CD8+ T cells were found to be HIV specific. However, high frequencies of HIV specific CD8+ T cells were not limited to LTNP with restriction of plasma virus. These data suggested that other qualitative parameters of the CD8+ T cell response may differentiate these patients. HLA typing revealed a dramatic association between the HLA B*5701 class I allele and nonprogressive infection (85% (11 of 13) vs 9.5% (19 of 200) in progressors; pless than 0.001). Although similar frequencies of HIV specific CD8+ T cells were found, the gag-specific CD8+ T cell response in the LTNP group was highly focused on peptides previously shown to be B*57 restricted. These findings indicated that within this phenotypically and genotypically distinct cohort, a host immune factor is highly associated with restriction of virus replication and nonprogressive disease. They also strongly suggest a mechanism of virus specific immunity that directly operates through the B*5701 molecule. Strong HIV specific CD4+ T cell proliferative responses are demonstrable in these LTNP patients. However, they are not demonstrable in the majority of infected patients with progressive disease. It has been presumed that HIV-specific CD4+ T cells are killed upon encountering antigen and maintenance of CD4+ T cell responses in some patients causes the restriction of virus replication. We have recently shown that although proliferative responses were absent in patients with poorly restricted virus replication, HIV-specific CD4+ T cells capable of producing interferon-gamma (IFN-g) were detected. In a separate cohort, interruption of antiretroviral therapy resulted in the rapid and complete abrogation of virus-specific proliferation although HIV-1-specific CD4+ T cells were present in the peripheral blood during viremia. Virus-specific proliferation returned when therapy was resumed and virus replication was controlled. Further, HIV-specific CD4+ T cells of viremic patients could be induced to proliferate in response to HIV antigens when co-stimulation was provided by anti-CD28 antibody in vitro. Thus, HIV-1-specific CD4+ T cells persist but remain poorly responsive (produce IFN-g but do not proliferate) in viremic patients. Unrestricted virus replication causes diminished proliferation of virus-specific CD4+ T cells. Suppression of proliferation of HIV-specific CD4+ T cells in the context of high levels of antigen is likely a critical mechanism by which HIV limits the precursor frequency of virus-specific CD4+ T cells and disrupts the development of an effective virus-specific immune response.